Pharmacology Of Diabetes Flashcards
What is the primary mechanism of action of Metformin?
Primary effect – metformin activates AMPK in hepatocyte mitochondria - inhibits ATP production, blocking gluconeogenesis and subsequent glucose output
Also blocks adenylate cyclase which promotes fat oxidation
Both help to restore insulin sensitivity
What is the drug target of Metformin?
5′-AMP-activated protein kinase (AMPK)
The primary site of metformin action is the hepatocyte mitochondria
What are the main side effects of Metformin?
GI side effects (20-30% of patients)
e.g. abdominal pain, decreased appetite, diarrhoea, vomiting
When are side effects of Metformin particularly evident and how can this be addressed?
Particularly evident when very high doses are given
A slow increase in dose may improve tolerability
Why does Metformin require a transporter to access tissues?
Highly polar
What transporter is required for Metformin to access tissues?
Organic cation transporter-1 (OCT-1)
Why can Metformin accumulate in the liver (therapeutic effect) and gastrointestinal tract (side effects)?
Because it requires the OCT-1 transporter (expressed by liver, small bowel and kidney) to access tissues
When is Metformin most effective?
Metformin is most effective in the presence of endogenous insulin so is most effective with some residual functioning pancreatic islet cells
Give an example of a DPP-4 inhibitor
Sitagliptin
What is the primary mechanism of action of DPP-4 inhibitors?
Work by inhibiting the action of dipeptidyl-peptidase 4 (DPP-4)
This enzyme is present in vascular endothelium and can metabolise incretins in the plasma
What do incretins do?
Incretins (e.g. GLP-1) are secreted by enteroendocrine cells:
- help stimulate the production of insulin when it is needed (e.g. after eating)
- reduce the production of glucagon by the liver when it is not needed (e.g. during digestion)
- also slow down digestion and decrease appetite
What is the drug target of DPP-4 inhibitors?
DPP-4
The primary site of DPP-4 inhibitor action is the vascular endothelium
What are the main side effects of DPP-4 inhibitors?
Upper respiratory tract infections (5% of patients)
Flu-like symptoms e.g. headache, runny nose, sore throat
Less common but serious:
Serious allergic reactions
Avoid in patients with pancreatitis
Do DPP-4 inhibitors appear to cause weight gain?
No, unlike other anti-diabetic drugs (not Metformin)
Would DPP-4 inhibitors be effective in patients with no residual insulin?
No
DPP-4 I’s act mainly by augmenting insulin secretion -> effective only when some residual pancreatic beta-cell activity is present
What is an example of a sulphonylurea?
Gliclazide
What is the primary mechanism of action of sulphonylurea?
Inhibits the ATP-sensitive potassium (KATP) channel on the pancreatic beta cell -> controls beta cell membrane potential
Inhibition causes depolarisation which stimulates Ca2+ influx and subsequent insulin vesicle exocytosis
What is the drug target of sulphonylureas?
ATP-sensitive potassium channel
The primary site of SUs inhibitor action is the pancreatic beta cell
What are the main side effects of sulphonylureas?
Weight gain is a likely side effect
Hypoglycaemia (2nd most common)
Why are SUs only effective when there is some residual pancreatic beta cell activity?
Act mainly by augmenting insulin secretion
How is weight gain mitigated when taking sulphonylureas?
Mitigated by concurrent administration with Metformin
Give an example of an SGLT2 inhibitor
Dapaglifozin
What is the main mechanism of action of SGLT2 inhibitors?
Reversibly inhibits sodium-glucose co-transporter 2 (SGLT2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion
What is the primary target of SGLT2 inhibitors?
SGLT2
The primary site of SGLT2 inhibitor action is the proximal convoluted tubule
What are the main side effects of SGLT2 inhibitors?
Uro-genital infections due to increased glucose load (5% of patients)
Slight decrease in bone formation
Can worsen diabetic ketoacidosis (stop immediately)
In which condition are SGLT2 inhibitors less effective?
Renal impairment
SGLT2i action depends on normal renal function
What other effects do SGLT2 inhibitors have on the body?
Weight loss
Reduction in BP
What is the relevance of OCT-1 expression in hepatocytes, enterocytes and proximal tubules to the pharmacokinetics of orally administered Metformin?
Small bowel OCT-1 allows absorption
Hepatocytes OCT-1 allows distribution to site of action
Proximal tubule OCT-1 helps excretion
